{"gene":"PRPF31","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2004,"finding":"RNAi knockdown of hPrp31 in HeLa cells inhibits U4/U6.U5 tri-snRNP formation, causing accumulation of stable U4/U6 di-snRNPs and U5 mono-snRNPs; the accumulated U4/U6 di-snRNPs localize to Cajal bodies, implicating Cajal bodies in tri-snRNP recycling.","method":"RNAi knockdown combined with biochemical fractionation and fluorescence microscopy","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal biochemical and imaging evidence from clean KD with defined cellular phenotype; moderate evidence from single lab with orthogonal methods","pmids":["15257298"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of the hPrp31 Nop domain in complex with 15.5K protein and U4 snRNA reveals that the Nop domain is a genuine RNP-binding module with distinct RNA and protein binding surfaces; it maintains high binding selectivity for U4/U6 snRNP over box C/D snoRNP complexes despite relaxed RNA sequence requirements. Yeast two-hybrid analyses also linked RP11 mutations to aberrant hPrp31–hPrp6 interaction that blocks tri-snRNP formation.","method":"X-ray crystallography of ternary hPrp31–15.5K–U4 snRNA complex; yeast two-hybrid assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional biochemical validation; strong mechanistic resolution","pmids":["17412961"],"is_preprint":false},{"year":2011,"finding":"Crystal structure analysis shows that the U4 and U4atac snRNA capping pentaloops adopt different conformations when bound to hPrp31–15.5K, with U4atac forming a noncanonical base pair that creates more intimate interactions with hPrp31 (including stacking of His270); rational mutagenesis confirmed the importance of these contacts, explaining dual U4/U4atac specificity of hPrp31.","method":"X-ray crystallography of ternary complexes with U4 and U4atac snRNAs; site-directed mutagenesis; gel-shift assays","journal":"RNA","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis plus functional gel-shift validation in one study","pmids":["21784869"],"is_preprint":false},{"year":1996,"finding":"PRP31 (yeast ortholog of PRPF31) encodes a ~60 kDa protein essential for cell viability and directly required for pre-mRNA splicing both in vivo and in vitro in Saccharomyces cerevisiae.","method":"Temperature-sensitive mutant screen; in vivo and in vitro splicing assays; epitope-tagging and Western analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — in vitro splicing reconstitution plus in vivo genetics; foundational characterization of the ortholog","pmids":["8604353"],"is_preprint":false},{"year":2002,"finding":"RP11-associated PRPF31 missense mutations A194E and A216P substantially hinder nuclear translocation of the protein in mammalian cells; the A216P mutation introduced into the yeast ortholog PRP31p only partially restores growth at restrictive temperature, indicating reduced splicing function; however, no dominant-negative effect on splicing was detected with a rhodopsin minigene assay, pointing to protein insufficiency as the disease mechanism.","method":"Yeast complementation assay; in vivo splicing assay in transfected human cells; Western blot; immunofluorescence microscopy","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (yeast genetics, mammalian splicing assay, localization) in single study","pmids":["12444105"],"is_preprint":false},{"year":2005,"finding":"Mutant PRPF31 proteins (A194E, A216P) significantly inhibit pre-mRNA splicing of rhodopsin (RHO) intron 3 as shown by immunoprecipitation of splicing complexes from retinal cells; PRPF31-containing complexes associate with RHO transcripts; expression of mutant PRPF31 reduces rhodopsin expression and causes apoptosis of rhodopsin-positive retinal cells in primary culture.","method":"Immunoprecipitation of splicing complexes + RT-PCR; minigene splicing assay; primary retinal cell culture with apoptosis readout","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — reciprocal IP plus functional splicing assay plus cellular phenotype with defined readout","pmids":["15659613"],"is_preprint":false},{"year":2007,"finding":"Immunoprecipitation-coupled microarray identified peripherin/RDS and FSCN2 transcripts associated with PRPF31-containing splicing complexes in photoreceptors; mutant PRPF31 proteins significantly inhibited pre-mRNA splicing of RDS and FSCN2 minigenes, establishing a functional link between the ubiquitous splicing factor PRPF31 and photoreceptor-specific gene expression.","method":"Immunoprecipitation-coupled microarray; minigene splicing assay","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 — IP-microarray plus minigene assay; single lab, moderate evidence","pmids":["17350276"],"is_preprint":false},{"year":2008,"finding":"Five of six PRPF31 patient mutations lead to premature termination codons that activate nonsense-mediated mRNA decay (NMD), resulting in strong reduction of mutant PRPF31 transcripts and absence of truncated proteins; blocking NMD partially restored mutant mRNA but not protein, indicating that most mutations act as null alleles through mRNA surveillance, establishing haploinsufficiency as the pathogenic mechanism.","method":"Allele-specific mRNA quantification; NMD inhibition (CHX, other inhibitors); Western blot; immunofluorescence in patient-derived cell lines","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in patient cells with defined molecular mechanism","pmids":["18317597"],"is_preprint":false},{"year":2008,"finding":"Pull-down assays showed that the RP11 missense mutation A216P in PRPF31 causes a stronger interaction with PRPF6 compared to wild-type, providing a mechanistic basis for a partial dominant-negative effect on splicing; splicing assays using full-length RHO template show 100% efficiency, whereas mini-gene assays detect reduced splicing, indicating protein insolubility/insufficiency as primary mechanism.","method":"Pull-down assay (PRPF31–PRPF6 interaction); in vivo splicing assay with RHO and GNAT1 minigene and full-length templates","journal":"Molecular vision","confidence":"Medium","confidence_rationale":"Tier 2–3 — single lab, pull-down plus splicing assay; consistent with broader literature","pmids":["18431455"],"is_preprint":false},{"year":2017,"finding":"PRP19 complex modifies PRPF31 with K63-linked ubiquitin chains; USP15, together with its substrate-targeting factor SART3, forms a complex with USP4 to deubiquitinate PRPF31 (and PRPF3); the ubiquitination/deubiquitination status of PRPF31 regulates its interaction with U5 snRNP component PRP8, which is required for efficient splicing of chromosome-segregation-related genes, likely by stabilizing the U4/U6.U5 tri-snRNP complex.","method":"Co-immunoprecipitation; in vitro ubiquitination assay; deubiquitinase assay; splicing assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro enzymatic assays plus reciprocal Co-IP plus functional splicing readout; strong mechanistic study","pmids":["28088760"],"is_preprint":false},{"year":2018,"finding":"Sf3A2 and Prp31 (Drosophila/human) bind spindle microtubules and the Ndc80 kinetochore complex; antibody injection into Drosophila embryos disrupts mitotic division within 1 minute (ruling out a splicing-related mechanism); depletion of Prp31 in HeLa cells causes chromosome segregation defects associated with reduced Ndc80/HEC1 at kinetochores; the Ndc80–Prp31 interaction is restricted to M phase in human cells.","method":"Anti-Prp31 antibody injection into Drosophila embryos; RNAi depletion in HeLa cells; Co-IP; microtubule co-sedimentation; kinetochore localization by immunofluorescence","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in two species; antibody injection provides rapid non-splicing-related functional evidence","pmids":["30475206"],"is_preprint":false},{"year":2012,"finding":"CNOT3, a subunit of the Ccr4-NOT transcription complex, directly binds to a specific PRPF31 promoter sequence (shown by chromatin immunoprecipitation) and transcriptionally represses PRPF31 expression; siRNA-mediated silencing of CNOT3 increases PRPF31 expression; lower CNOT3 levels in asymptomatic PRPF31 mutation carriers permit higher wild-type PRPF31 expression, explaining incomplete penetrance.","method":"Chromatin immunoprecipitation (ChIP); siRNA silencing of CNOT3; mRNA/protein quantification in patient-derived cell lines; next-generation sequencing of CNOT3 region","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — ChIP plus siRNA functional experiment in patient cells; replicated correlation across cell lines","pmids":["23144630"],"is_preprint":false},{"year":2018,"finding":"Transcriptome profiling of RP11 (PRPF31-mutated) patient-derived retinal organoids, RPE and Prpf31+/- mouse tissues revealed that disrupted alternative splicing occurs for specific programmes: mis-splicing of pre-mRNA splicing factor genes is restricted to retinal cells, while mis-splicing of ciliogenesis and cell adhesion genes is associated with RPE defects including disrupted apical-basal polarity, reduced trans-epithelial resistance, reduced phagocytosis, and decreased cilia length. In situ gene editing of pathogenic mutation rescued protein expression and key phenotypes.","method":"Transcriptome profiling (RNA-seq) of patient-derived retinal organoids and RPE; Prpf31+/- mouse retinal analyses; CRISPR/Cas9 gene editing rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — transcriptome-wide analysis combined with multiple functional readouts and gene-editing rescue in patient cells and mouse model","pmids":["30315276"],"is_preprint":false},{"year":2021,"finding":"In prpf31 knockout zebrafish, retinal progenitor cells (RPCs) show mitotic arrest, DNA damage, and failure of differentiation at an early embryonic stage while other tissues are less affected; these defects are rescued by wild-type human PRPF31 but not disease-associated mutants; bioinformatic analysis showed that Prpf31 deletion predominantly causes exon skipping at weak 5' splice sites, particularly in genes required for DNA repair and mitotic progression.","method":"Zebrafish prpf31 knockout; rescue by wild-type vs. mutant human PRPF31; transcriptome-wide splicing analysis; cell biology assays (mitotic arrest, DNA damage markers)","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function zebrafish model with defined cellular phenotype plus rescue experiment with mutant vs. WT protein and transcriptome-wide splicing analysis","pmids":["33476374"],"is_preprint":false},{"year":2011,"finding":"The SP117 PRPF31 mutation produces an unstable, cytoplasm-mislocalized protein; its overexpression does not cause photoreceptor degeneration in zebrafish, supporting haploinsufficiency as the disease mechanism. The AD5 mutation produces a stable protein initially nuclear but later found in the cytoplasm concurrent with rod outer segment degeneration; overexpression of AD5 causes embryonic lethality rescued by wild-type Prpf31; retinal transcripts are wrongly spliced in transgenic AD5 retinas with increased apoptosis, demonstrating in vivo that aberrant splicing contributes to retinal defects via a dominant-negative mechanism.","method":"Zebrafish overexpression and transgenic retina-specific expression; immunolocalization; in vivo RT-PCR splicing analysis; lethality rescue assay","journal":"Molecular neurodegeneration","confidence":"High","confidence_rationale":"Tier 2 — in vivo splicing evidence plus localization plus rescue experiment; first in vivo splicing defect demonstration for PRPF31","pmids":["21801444"],"is_preprint":false},{"year":2009,"finding":"Prpf31A216P/A216P and Prpf31-/- genotypes are embryonic lethal in mice, demonstrating that Prpf31 is essential for survival and that there is no compensating mechanism for its complete loss; heterozygous Prpf31A216P/+ and Prpf31+/- mice show no retinal degenerative phenotype, suggesting that one wild-type allele is sufficient for retinal health in mice and that the p.A216P mutation does not exert a dominant-negative effect in this model.","method":"Gene-targeted knock-in and knockout mouse models; ERG; retinal histology; fundus examination","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 2 — clean KO/KI mouse models with defined phenotypic readouts; embryonic lethality robustly established","pmids":["19578015"],"is_preprint":false},{"year":2019,"finding":"Mutant PRPF31 protein (A216P) forms cytoplasmic aggregates in RPE cells, sequestering normal PRPF31 into insoluble fractions and reducing nuclear PRPF31 levels; in response, the HSP70 family chaperone Hspa4l is overexpressed and may facilitate folding and nuclear translocation of mutant protein. Co-expression of mutant and wild-type PRPF31 in vitro shows the mutant recruits normal protein into insoluble aggregates, supporting a combined haploinsufficiency/dominant-negative mechanism.","method":"Mouse model analysis (Prpf31A216P); immunofluorescence; biochemical fractionation (soluble/insoluble); in vitro co-overexpression; Western blot","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 — in vivo and in vitro protein aggregation evidence; single lab with multiple methods","pmids":["31892304"],"is_preprint":false},{"year":2016,"finding":"PRPF31 knockdown by siRNA in HBV-replicating cells decreased cccDNA formation without major cytotoxicity; siRNA-resistant PRPF31 rescued cccDNA formation; chromatin immunoprecipitation and immunoprecipitation assays revealed a physical association between PRPF31 and HBV cccDNA; co-overexpression of PRPF31 and HBx enhanced cccDNA formation, suggesting PRPF31–HBx interaction promotes cccDNA production.","method":"siRNA knockdown; rescue experiment with siRNA-resistant PRPF31; ChIP assay; co-immunoprecipitation; overexpression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 — ChIP and co-IP plus functional rescue; single lab; novel role outside canonical splicing","pmids":["27864147"],"is_preprint":false},{"year":2012,"finding":"Luciferase reporter assays identified core promoter elements for PRPF31; one functional polymorphism in the PRPF31 promoter increased transcriptional activation; a patient regulatory-region mutation reduced promoter activity by >50%, establishing a mechanism of functional haploinsufficiency at the transcriptional level.","method":"Dual-luciferase reporter assay in HeLa and RPE-1 cells; patient-derived genomic DNA constructs","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 — reporter assay with patient-derived constructs; single lab, single method type","pmids":["22723017"],"is_preprint":false},{"year":2005,"finding":"In fission yeast (S. pombe), Prp31 is complexed with Prp1 and Brr2 in large pre-catalytic spliceosomal particles (30S–60S) containing all five snRNAs; Prp1 and Prp31 co-sediment in the same particles, and cells lacking Prp1 still contain these Prp31-associated particles, suggesting Prp31 participates in pre-catalytic spliceosome assembly independently of Prp1 phosphorylation.","method":"Co-sedimentation/sucrose gradient fractionation; co-immunoprecipitation; genetic suppressor analysis in S. pombe","journal":"Current genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 — biochemical co-fractionation plus genetic interaction in fission yeast ortholog","pmids":["16133344"],"is_preprint":false},{"year":2000,"finding":"In fission yeast, prp31+ is essential for vegetative growth and meiotic progression; a temperature-sensitive prp31-E1 allele displays pre-mRNA splicing defects and is synthetically lethal with prp6, establishing Prp31 as a general splicing factor functioning in both vegetative and meiotic contexts.","method":"Temperature-sensitive mutant isolation; complementation cloning; synthetic lethality assay with prp6; pre-mRNA splicing assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis (synthetic lethality with prp6) plus in vivo splicing assay in fission yeast ortholog","pmids":["10871341"],"is_preprint":false},{"year":2019,"finding":"AAV-mediated delivery of wild-type PRPF31 to iPSC-derived RPE cells from PRPF31-mutant patients restored normal phagocytosis and cilia formation, and partially restored cell structure and barrier function, demonstrating that increasing wild-type PRPF31 protein levels is sufficient to rescue RPE functional defects.","method":"AAV gene augmentation in iPSC-derived RPE; phagocytosis assay; ciliogenesis assay; transepithelial resistance measurement; immunofluorescence","journal":"Molecular therapy. Methods & clinical development","confidence":"Medium","confidence_rationale":"Tier 2 — functional rescue with defined cellular phenotypes in patient-derived cells; single lab","pmids":["31890732"],"is_preprint":false},{"year":2022,"finding":"AAV-mediated PRPF31 gene augmentation in a CRISPR/Cas9-based Prpf31 knockout mouse model restored retinal structure and function (ERG responses), providing the first in vivo proof-of-concept for AAV gene therapy to treat PRPF31-retinitis pigmentosa.","method":"AAV-CRISPR/Cas9 knockout mouse model; AAV-PRPF31 gene augmentation; ERG; OCT; histology","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — in vivo gene therapy rescue in de novo mouse model with functional and structural readouts","pmids":["36509783"],"is_preprint":false}],"current_model":"PRPF31 encodes an essential U4/U6 snRNP component whose Nop domain binds a composite RNP platform formed by the 15.5K protein and U4 (or U4atac) snRNA; it bridges U4/U6 and U5 snRNPs to enable U4/U6.U5 tri-snRNP assembly, a process regulated by PRP19-mediated K63-ubiquitination and USP15/SART3-mediated deubiquitination of PRPF31; heterozygous loss-of-function mutations cause retinitis pigmentosa primarily through haploinsufficiency (NMD of mutant transcripts, nuclear translocation defects, or protein aggregation that sequesters wild-type protein), with penetrance modulated by wild-type allele expression levels controlled in part by the transcriptional repressor CNOT3; additionally, PRPF31 has a splicing-independent role in mitosis by directly binding spindle microtubules and the Ndc80 kinetochore complex to regulate chromosome segregation."},"narrative":{"teleology":[{"year":1996,"claim":"Establishing PRPF31 as an essential splicing factor: the yeast ortholog PRP31 was shown to be required for cell viability and directly needed for pre-mRNA splicing both in vivo and in vitro, defining the gene's core cellular function.","evidence":"Temperature-sensitive mutant screen with in vivo and in vitro splicing assays in S. cerevisiae","pmids":["8604353"],"confidence":"High","gaps":["Human ortholog function not yet tested","Position within spliceosomal subcomplex unknown","No structural information"]},{"year":2000,"claim":"Genetic interaction with PRP6 and essentiality in both vegetative and meiotic contexts were established in fission yeast, positioning Prp31 as a general splicing factor with functional links to tri-snRNP assembly components.","evidence":"Synthetic lethality of prp31 with prp6 and splicing assays in S. pombe","pmids":["10871341"],"confidence":"Medium","gaps":["Biochemical basis of Prp31–Prp6 interaction unresolved","Whether meiotic defect is direct or secondary to splicing failure unknown"]},{"year":2002,"claim":"The question of how RP11 mutations cause disease was addressed: missense mutations A194E and A216P impair nuclear translocation without exerting dominant-negative effects on splicing, pointing to protein insufficiency rather than toxic gain-of-function.","evidence":"Yeast complementation, mammalian immunofluorescence, and rhodopsin minigene splicing assay","pmids":["12444105"],"confidence":"High","gaps":["Mechanism of nuclear import failure not defined","Whether all RP11 mutations act via same mechanism unknown"]},{"year":2004,"claim":"PRPF31's specific role in tri-snRNP biogenesis was defined: its depletion blocks the U4/U6-to-U4/U6.U5 transition, causing U4/U6 di-snRNP accumulation in Cajal bodies, establishing PRPF31 as the bridge between di-snRNP and U5 snRNP.","evidence":"RNAi knockdown in HeLa cells with glycerol gradient fractionation and fluorescence microscopy","pmids":["15257298"],"confidence":"High","gaps":["Direct binding partners mediating the bridging step not identified","Role of Cajal body accumulation unclear"]},{"year":2005,"claim":"Linking PRPF31 dysfunction to retinal gene expression: mutant PRPF31 inhibits splicing of rhodopsin transcripts and causes photoreceptor apoptosis, providing the first direct mechanistic connection between a ubiquitous splicing factor mutation and retina-specific pathology.","evidence":"Immunoprecipitation of splicing complexes with RT-PCR and apoptosis assays in primary retinal cells","pmids":["15659613"],"confidence":"High","gaps":["Why retinal transcripts are selectively vulnerable not explained","In vivo retinal splicing defects not yet demonstrated"]},{"year":2007,"claim":"Structural basis of PRPF31 RNA recognition was solved: the Nop domain crystal structure in complex with 15.5K and U4 snRNA revealed it as a dedicated RNP-binding module with distinct RNA and protein interaction surfaces, and RP11 mutations were linked to aberrant PRPF6 interaction.","evidence":"X-ray crystallography of the ternary hPrp31–15.5K–U4 snRNA complex; yeast two-hybrid analysis of RP11 mutants","pmids":["17412961"],"confidence":"High","gaps":["Full-length PRPF31 structure not available","Structural basis of PRPF31–PRPF6 interaction not resolved"]},{"year":2008,"claim":"The haploinsufficiency mechanism was firmly established: most RP11 mutations create premature stop codons degraded by NMD, producing functional null alleles, confirming that disease arises from reduced wild-type protein rather than toxic mutant protein.","evidence":"Allele-specific mRNA quantification with NMD inhibition in patient-derived cell lines","pmids":["18317597"],"confidence":"High","gaps":["Why 50% protein reduction is pathogenic specifically in retina not resolved","Contribution of rare dominant-negative mutations not fully excluded"]},{"year":2011,"claim":"Dual snRNA specificity was structurally explained: U4 and U4atac pentaloops adopt distinct conformations when bound to PRPF31–15.5K, with U4atac forming additional contacts including His270 stacking, explaining how PRPF31 serves both major and minor spliceosomes.","evidence":"X-ray crystallography of both ternary complexes with mutagenesis and gel-shift validation","pmids":["21784869"],"confidence":"High","gaps":["Functional consequences of differential affinity for U4 vs U4atac in vivo not tested"]},{"year":2012,"claim":"The long-standing puzzle of incomplete RP11 penetrance was solved: CNOT3 was identified as a transcriptional repressor of PRPF31, with lower CNOT3 levels in asymptomatic carriers permitting higher wild-type allele expression that compensates for the null allele.","evidence":"ChIP showing CNOT3 binding to PRPF31 promoter; siRNA knockdown of CNOT3 increasing PRPF31 expression; correlation in patient-derived cell lines","pmids":["23144630"],"confidence":"High","gaps":["Other trans-acting modifiers of PRPF31 expression not surveyed","Mechanism of CNOT3 expression variation between individuals unknown"]},{"year":2017,"claim":"Post-translational regulation of PRPF31 was uncovered: PRP19-mediated K63-ubiquitination and USP15/SART3-mediated deubiquitination control PRPF31's interaction with PRP8 and thus tri-snRNP stability and splicing efficiency.","evidence":"In vitro ubiquitination and deubiquitinase assays, co-immunoprecipitation, and splicing assays","pmids":["28088760"],"confidence":"High","gaps":["Specific ubiquitinated lysine residues on PRPF31 not mapped","Whether ubiquitination status is dynamically regulated across the cell cycle unknown"]},{"year":2018,"claim":"A splicing-independent mitotic function was discovered: PRPF31 directly binds spindle microtubules and the Ndc80 kinetochore complex during M phase, and its acute inhibition by antibody injection causes immediate chromosome segregation defects too rapid to reflect splicing changes.","evidence":"Antibody injection in Drosophila embryos; RNAi in HeLa cells; co-IP and microtubule co-sedimentation; M-phase-restricted interaction","pmids":["30475206"],"confidence":"High","gaps":["Structural basis of PRPF31–Ndc80 interaction not determined","Whether this mitotic role contributes to RP11 pathology unknown","Mechanism of cell-cycle-restricted interaction not defined"]},{"year":2018,"claim":"Tissue-specific splicing programmes disrupted by PRPF31 haploinsufficiency were mapped: retinal cells show mis-splicing of splicing factor genes themselves, while RPE cells show mis-splicing of ciliogenesis and adhesion genes with corresponding functional defects rescued by gene editing.","evidence":"RNA-seq of patient-derived retinal organoids and RPE; Prpf31+/- mouse retina; CRISPR/Cas9 rescue","pmids":["30315276"],"confidence":"High","gaps":["Why splicing factor transcripts are selectively vulnerable in retinal neurons not mechanistically explained","Contribution of individual mis-spliced transcripts to degeneration not isolated"]},{"year":2019,"claim":"Protein aggregation was identified as an additional pathogenic mechanism: the A216P mutant forms cytoplasmic aggregates that sequester wild-type PRPF31 into insoluble fractions, supporting a combined haploinsufficiency/dominant-negative model for missense mutations.","evidence":"Biochemical fractionation and co-overexpression in Prpf31-A216P mouse model and in vitro","pmids":["31892304"],"confidence":"Medium","gaps":["Aggregation not demonstrated for other RP11 missense mutations","Whether chaperone (Hspa4l) upregulation is protective in vivo not established"]},{"year":2022,"claim":"Therapeutic proof-of-concept was achieved: AAV-mediated PRPF31 gene augmentation restored retinal structure and function in a CRISPR-generated Prpf31 knockout mouse, validating haploinsufficiency as the targetable disease mechanism.","evidence":"AAV-PRPF31 delivery in Prpf31 KO mice with ERG, OCT, and histological readouts","pmids":["36509783"],"confidence":"High","gaps":["Long-term durability of AAV-mediated rescue not established","Optimal therapeutic window and dose–response not defined"]},{"year":null,"claim":"Key open questions include how PRPF31's mitotic kinetochore function relates to retinal disease, which specific retinal transcripts are rate-limiting for photoreceptor survival under haploinsufficiency, and whether the ubiquitination cycle is a druggable axis for modulating tri-snRNP assembly.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of full-length PRPF31 in the context of the human tri-snRNP","Mechanism by which retinal cells are uniquely sensitive to 50% reduction unknown","Relationship between mitotic and splicing functions not dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[10]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4,7]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[10]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,3,9,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[10,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,12,22]}],"complexes":["U4/U6 di-snRNP","U4/U6.U5 tri-snRNP","15.5K–U4 snRNA ternary complex"],"partners":["SNU13","PRPF6","PRPF8","USP15","SART3","PRPF19","NDC80","CNOT3"],"other_free_text":[]},"mechanistic_narrative":"PRPF31 is an essential pre-mRNA splicing factor that bridges the U4/U6 di-snRNP to U5 snRNP, enabling assembly of the catalytic U4/U6.U5 tri-snRNP required for spliceosome activation. Its Nop domain recognizes a composite ribonucleoprotein surface formed by the 15.5K protein and U4 (or U4atac) snRNA, with specificity governed by structural differences in the snRNA capping pentaloop, and its activity is regulated by PRP19-mediated K63-linked ubiquitination and USP15/SART3-mediated deubiquitination that control its interaction with the U5 component PRP8 [PMID:17412961, PMID:21784869, PMID:28088760, PMID:15257298]. Beyond splicing, PRPF31 directly binds spindle microtubules and the Ndc80 kinetochore complex during mitosis to promote accurate chromosome segregation, a function too rapid to be explained by transcript-level effects [PMID:30475206]. Heterozygous loss-of-function mutations cause autosomal dominant retinitis pigmentosa (RP11) primarily through haploinsufficiency—most mutations generate premature termination codons degraded by nonsense-mediated decay—with disease penetrance modulated by wild-type allele expression levels controlled in part by the transcriptional repressor CNOT3 [PMID:18317597, PMID:23144630, PMID:30315276]."},"prefetch_data":{"uniprot":{"accession":"Q8WWY3","full_name":"U4/U6 small nuclear ribonucleoprotein Prp31","aliases":["Pre-mRNA-processing factor 31","Serologically defined breast cancer antigen NY-BR-99","U4/U6 snRNP 61 kDa protein","Protein 61K","hPrp31"],"length_aa":499,"mass_kda":55.5,"function":"Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11867543, PubMed:20118938, PubMed:28781166). Required for the assembly of the U4/U5/U6 tri-snRNP complex, one of the building blocks of the spliceosome (PubMed:11867543)","subcellular_location":"Nucleus; Nucleus speckle; Nucleus, Cajal body","url":"https://www.uniprot.org/uniprotkb/Q8WWY3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PRPF31","classification":"Common 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physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30203513","citation_count":17,"is_preprint":false},{"pmid":"34195276","id":"PMC_34195276","title":"Long Noncoding RNA RP11-357H14.17 Plays an Oncogene Role in Gastric Cancer by Activating ATF2 Signaling and Enhancing Treg Cells.","date":"2021","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/34195276","citation_count":17,"is_preprint":false},{"pmid":"22723017","id":"PMC_22723017","title":"Expression of PRPF31 and TFPT: regulation in health and retinal disease.","date":"2012","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22723017","citation_count":17,"is_preprint":false},{"pmid":"30099644","id":"PMC_30099644","title":"A novel mutation in the PRPF31 in a North Indian adRP family with incomplete penetrance.","date":"2018","source":"Documenta ophthalmologica. Advances in ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/30099644","citation_count":16,"is_preprint":false},{"pmid":"31397491","id":"PMC_31397491","title":"RP11-284F21.9 promotes oral squamous cell carcinoma development via the miR-383-5p/MAL2 axis.","date":"2019","source":"Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31397491","citation_count":16,"is_preprint":false},{"pmid":"34469785","id":"PMC_34469785","title":"Long non-coding RNA RP11-490M8.1 inhibits lipopolysaccharide-induced pyroptosis of human umbilical vein endothelial cells via the TLR4/NF-κB pathway.","date":"2021","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/34469785","citation_count":16,"is_preprint":false},{"pmid":"32985313","id":"PMC_32985313","title":"Exploring microperimetry and autofluorescence endpoints for monitoring disease progression in PRPF31-associated retinopathy.","date":"2020","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32985313","citation_count":15,"is_preprint":false},{"pmid":"34130584","id":"PMC_34130584","title":"Long non-coding RNA RP11-283G6.5 confines breast cancer development through modulating miR-188-3p/TMED3/Wnt/β-catenin signalling.","date":"2021","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/34130584","citation_count":15,"is_preprint":false},{"pmid":"24319336","id":"PMC_24319336","title":"Two novel PRP31 premessenger ribonucleic acid processing factor 31 homolog mutations including a complex insertion-deletion identified in Chinese families with retinitis pigmentosa.","date":"2013","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/24319336","citation_count":15,"is_preprint":false},{"pmid":"36576700","id":"PMC_36576700","title":"H3K27 acetylation activated long noncoding RNA RP11-162G10.5 promotes breast cancer progression via the YBX1/GLO1 axis.","date":"2022","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/36576700","citation_count":15,"is_preprint":false},{"pmid":"29143419","id":"PMC_29143419","title":"Long Noncoding RNA RP11-380D23.2 Drives Distal-Proximal Patterning of the Lung by Regulating PITX2 Expression.","date":"2017","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/29143419","citation_count":15,"is_preprint":false},{"pmid":"19373678","id":"PMC_19373678","title":"PRPF31 alternative splicing and expression in human retina.","date":"2009","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19373678","citation_count":14,"is_preprint":false},{"pmid":"37370092","id":"PMC_37370092","title":"RP11-296E3.2 acts as an important molecular chaperone for YBX1 and promotes colorectal cancer proliferation and metastasis by activating STAT3.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37370092","citation_count":14,"is_preprint":false},{"pmid":"29256224","id":"PMC_29256224","title":"[Effects of lncRNA RP11-770J1.3 and TMEM25 expression on paclitaxel resistance in human breast cancer cells].","date":"2017","source":"Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29256224","citation_count":14,"is_preprint":false},{"pmid":"31283072","id":"PMC_31283072","title":"Rs2262251 in lncRNA RP11-462G12.2 is associated with nonsyndromic cleft lip with/without cleft palate.","date":"2019","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/31283072","citation_count":14,"is_preprint":false},{"pmid":"34621737","id":"PMC_34621737","title":"LncRNA RP11-499E18.1 Inhibits Proliferation, Migration, and Epithelial-Mesenchymal Transition Process of Ovarian Cancer Cells by Dissociating PAK2-SOX2 Interaction.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34621737","citation_count":14,"is_preprint":false},{"pmid":"10871341","id":"PMC_10871341","title":"Isolation of an essential Schizosaccharomyces pombe gene, prp31(+), that links splicing and meiosis.","date":"2000","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/10871341","citation_count":13,"is_preprint":false},{"pmid":"34198599","id":"PMC_34198599","title":"Clinical Evidence for the Importance of the Wild-Type PRPF31 Allele in the Phenotypic Expression of RP11.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/34198599","citation_count":13,"is_preprint":false},{"pmid":"36092938","id":"PMC_36092938","title":"LncRNA RP11-59J16.2 aggravates apoptosis and increases tau phosphorylation by targeting MCM2 in AD.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36092938","citation_count":13,"is_preprint":false},{"pmid":"30335897","id":"PMC_30335897","title":"Dependence of artesunate on long noncoding RNA-RP11 to inhibit epithelial-mesenchymal transition of hepatocellular carcinoma.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30335897","citation_count":13,"is_preprint":false},{"pmid":"27381066","id":"PMC_27381066","title":"Span poly-L-arginine nanoparticles are efficient non-viral vectors for PRPF31 gene delivery: An approach of gene therapy to treat retinitis pigmentosa.","date":"2016","source":"Nanomedicine : nanotechnology, biology, and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27381066","citation_count":13,"is_preprint":false},{"pmid":"32733789","id":"PMC_32733789","title":"Long Non-coding RNA RP11-480I12.5 Promotes the Proliferation, Migration, and Invasion of Breast Cancer Cells Through the miR-490-3p-AURKA-Wnt/β-Catenin Axis.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32733789","citation_count":13,"is_preprint":false},{"pmid":"37714045","id":"PMC_37714045","title":"PRPF31-retinitis pigmentosa: Challenges and opportunities for clinical translation.","date":"2023","source":"Vision research","url":"https://pubmed.ncbi.nlm.nih.gov/37714045","citation_count":12,"is_preprint":false},{"pmid":"27864147","id":"PMC_27864147","title":"Host factor PRPF31 is involved in cccDNA production in HBV-replicating cells.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27864147","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53275,"output_tokens":6050,"usd":0.125287},"stage2":{"model":"claude-opus-4-6","input_tokens":9627,"output_tokens":3575,"usd":0.206265},"total_usd":0.331552,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"RNAi knockdown of hPrp31 in HeLa cells inhibits U4/U6.U5 tri-snRNP formation, causing accumulation of stable U4/U6 di-snRNPs and U5 mono-snRNPs; the accumulated U4/U6 di-snRNPs localize to Cajal bodies, implicating Cajal bodies in tri-snRNP recycling.\",\n      \"method\": \"RNAi knockdown combined with biochemical fractionation and fluorescence microscopy\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal biochemical and imaging evidence from clean KD with defined cellular phenotype; moderate evidence from single lab with orthogonal methods\",\n      \"pmids\": [\"15257298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of the hPrp31 Nop domain in complex with 15.5K protein and U4 snRNA reveals that the Nop domain is a genuine RNP-binding module with distinct RNA and protein binding surfaces; it maintains high binding selectivity for U4/U6 snRNP over box C/D snoRNP complexes despite relaxed RNA sequence requirements. Yeast two-hybrid analyses also linked RP11 mutations to aberrant hPrp31–hPrp6 interaction that blocks tri-snRNP formation.\",\n      \"method\": \"X-ray crystallography of ternary hPrp31–15.5K–U4 snRNA complex; yeast two-hybrid assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional biochemical validation; strong mechanistic resolution\",\n      \"pmids\": [\"17412961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure analysis shows that the U4 and U4atac snRNA capping pentaloops adopt different conformations when bound to hPrp31–15.5K, with U4atac forming a noncanonical base pair that creates more intimate interactions with hPrp31 (including stacking of His270); rational mutagenesis confirmed the importance of these contacts, explaining dual U4/U4atac specificity of hPrp31.\",\n      \"method\": \"X-ray crystallography of ternary complexes with U4 and U4atac snRNAs; site-directed mutagenesis; gel-shift assays\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis plus functional gel-shift validation in one study\",\n      \"pmids\": [\"21784869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"PRP31 (yeast ortholog of PRPF31) encodes a ~60 kDa protein essential for cell viability and directly required for pre-mRNA splicing both in vivo and in vitro in Saccharomyces cerevisiae.\",\n      \"method\": \"Temperature-sensitive mutant screen; in vivo and in vitro splicing assays; epitope-tagging and Western analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro splicing reconstitution plus in vivo genetics; foundational characterization of the ortholog\",\n      \"pmids\": [\"8604353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"RP11-associated PRPF31 missense mutations A194E and A216P substantially hinder nuclear translocation of the protein in mammalian cells; the A216P mutation introduced into the yeast ortholog PRP31p only partially restores growth at restrictive temperature, indicating reduced splicing function; however, no dominant-negative effect on splicing was detected with a rhodopsin minigene assay, pointing to protein insufficiency as the disease mechanism.\",\n      \"method\": \"Yeast complementation assay; in vivo splicing assay in transfected human cells; Western blot; immunofluorescence microscopy\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (yeast genetics, mammalian splicing assay, localization) in single study\",\n      \"pmids\": [\"12444105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mutant PRPF31 proteins (A194E, A216P) significantly inhibit pre-mRNA splicing of rhodopsin (RHO) intron 3 as shown by immunoprecipitation of splicing complexes from retinal cells; PRPF31-containing complexes associate with RHO transcripts; expression of mutant PRPF31 reduces rhodopsin expression and causes apoptosis of rhodopsin-positive retinal cells in primary culture.\",\n      \"method\": \"Immunoprecipitation of splicing complexes + RT-PCR; minigene splicing assay; primary retinal cell culture with apoptosis readout\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal IP plus functional splicing assay plus cellular phenotype with defined readout\",\n      \"pmids\": [\"15659613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Immunoprecipitation-coupled microarray identified peripherin/RDS and FSCN2 transcripts associated with PRPF31-containing splicing complexes in photoreceptors; mutant PRPF31 proteins significantly inhibited pre-mRNA splicing of RDS and FSCN2 minigenes, establishing a functional link between the ubiquitous splicing factor PRPF31 and photoreceptor-specific gene expression.\",\n      \"method\": \"Immunoprecipitation-coupled microarray; minigene splicing assay\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — IP-microarray plus minigene assay; single lab, moderate evidence\",\n      \"pmids\": [\"17350276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Five of six PRPF31 patient mutations lead to premature termination codons that activate nonsense-mediated mRNA decay (NMD), resulting in strong reduction of mutant PRPF31 transcripts and absence of truncated proteins; blocking NMD partially restored mutant mRNA but not protein, indicating that most mutations act as null alleles through mRNA surveillance, establishing haploinsufficiency as the pathogenic mechanism.\",\n      \"method\": \"Allele-specific mRNA quantification; NMD inhibition (CHX, other inhibitors); Western blot; immunofluorescence in patient-derived cell lines\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in patient cells with defined molecular mechanism\",\n      \"pmids\": [\"18317597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Pull-down assays showed that the RP11 missense mutation A216P in PRPF31 causes a stronger interaction with PRPF6 compared to wild-type, providing a mechanistic basis for a partial dominant-negative effect on splicing; splicing assays using full-length RHO template show 100% efficiency, whereas mini-gene assays detect reduced splicing, indicating protein insolubility/insufficiency as primary mechanism.\",\n      \"method\": \"Pull-down assay (PRPF31–PRPF6 interaction); in vivo splicing assay with RHO and GNAT1 minigene and full-length templates\",\n      \"journal\": \"Molecular vision\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — single lab, pull-down plus splicing assay; consistent with broader literature\",\n      \"pmids\": [\"18431455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PRP19 complex modifies PRPF31 with K63-linked ubiquitin chains; USP15, together with its substrate-targeting factor SART3, forms a complex with USP4 to deubiquitinate PRPF31 (and PRPF3); the ubiquitination/deubiquitination status of PRPF31 regulates its interaction with U5 snRNP component PRP8, which is required for efficient splicing of chromosome-segregation-related genes, likely by stabilizing the U4/U6.U5 tri-snRNP complex.\",\n      \"method\": \"Co-immunoprecipitation; in vitro ubiquitination assay; deubiquitinase assay; splicing assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro enzymatic assays plus reciprocal Co-IP plus functional splicing readout; strong mechanistic study\",\n      \"pmids\": [\"28088760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Sf3A2 and Prp31 (Drosophila/human) bind spindle microtubules and the Ndc80 kinetochore complex; antibody injection into Drosophila embryos disrupts mitotic division within 1 minute (ruling out a splicing-related mechanism); depletion of Prp31 in HeLa cells causes chromosome segregation defects associated with reduced Ndc80/HEC1 at kinetochores; the Ndc80–Prp31 interaction is restricted to M phase in human cells.\",\n      \"method\": \"Anti-Prp31 antibody injection into Drosophila embryos; RNAi depletion in HeLa cells; Co-IP; microtubule co-sedimentation; kinetochore localization by immunofluorescence\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in two species; antibody injection provides rapid non-splicing-related functional evidence\",\n      \"pmids\": [\"30475206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CNOT3, a subunit of the Ccr4-NOT transcription complex, directly binds to a specific PRPF31 promoter sequence (shown by chromatin immunoprecipitation) and transcriptionally represses PRPF31 expression; siRNA-mediated silencing of CNOT3 increases PRPF31 expression; lower CNOT3 levels in asymptomatic PRPF31 mutation carriers permit higher wild-type PRPF31 expression, explaining incomplete penetrance.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP); siRNA silencing of CNOT3; mRNA/protein quantification in patient-derived cell lines; next-generation sequencing of CNOT3 region\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus siRNA functional experiment in patient cells; replicated correlation across cell lines\",\n      \"pmids\": [\"23144630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Transcriptome profiling of RP11 (PRPF31-mutated) patient-derived retinal organoids, RPE and Prpf31+/- mouse tissues revealed that disrupted alternative splicing occurs for specific programmes: mis-splicing of pre-mRNA splicing factor genes is restricted to retinal cells, while mis-splicing of ciliogenesis and cell adhesion genes is associated with RPE defects including disrupted apical-basal polarity, reduced trans-epithelial resistance, reduced phagocytosis, and decreased cilia length. In situ gene editing of pathogenic mutation rescued protein expression and key phenotypes.\",\n      \"method\": \"Transcriptome profiling (RNA-seq) of patient-derived retinal organoids and RPE; Prpf31+/- mouse retinal analyses; CRISPR/Cas9 gene editing rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — transcriptome-wide analysis combined with multiple functional readouts and gene-editing rescue in patient cells and mouse model\",\n      \"pmids\": [\"30315276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In prpf31 knockout zebrafish, retinal progenitor cells (RPCs) show mitotic arrest, DNA damage, and failure of differentiation at an early embryonic stage while other tissues are less affected; these defects are rescued by wild-type human PRPF31 but not disease-associated mutants; bioinformatic analysis showed that Prpf31 deletion predominantly causes exon skipping at weak 5' splice sites, particularly in genes required for DNA repair and mitotic progression.\",\n      \"method\": \"Zebrafish prpf31 knockout; rescue by wild-type vs. mutant human PRPF31; transcriptome-wide splicing analysis; cell biology assays (mitotic arrest, DNA damage markers)\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function zebrafish model with defined cellular phenotype plus rescue experiment with mutant vs. WT protein and transcriptome-wide splicing analysis\",\n      \"pmids\": [\"33476374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The SP117 PRPF31 mutation produces an unstable, cytoplasm-mislocalized protein; its overexpression does not cause photoreceptor degeneration in zebrafish, supporting haploinsufficiency as the disease mechanism. The AD5 mutation produces a stable protein initially nuclear but later found in the cytoplasm concurrent with rod outer segment degeneration; overexpression of AD5 causes embryonic lethality rescued by wild-type Prpf31; retinal transcripts are wrongly spliced in transgenic AD5 retinas with increased apoptosis, demonstrating in vivo that aberrant splicing contributes to retinal defects via a dominant-negative mechanism.\",\n      \"method\": \"Zebrafish overexpression and transgenic retina-specific expression; immunolocalization; in vivo RT-PCR splicing analysis; lethality rescue assay\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo splicing evidence plus localization plus rescue experiment; first in vivo splicing defect demonstration for PRPF31\",\n      \"pmids\": [\"21801444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Prpf31A216P/A216P and Prpf31-/- genotypes are embryonic lethal in mice, demonstrating that Prpf31 is essential for survival and that there is no compensating mechanism for its complete loss; heterozygous Prpf31A216P/+ and Prpf31+/- mice show no retinal degenerative phenotype, suggesting that one wild-type allele is sufficient for retinal health in mice and that the p.A216P mutation does not exert a dominant-negative effect in this model.\",\n      \"method\": \"Gene-targeted knock-in and knockout mouse models; ERG; retinal histology; fundus examination\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/KI mouse models with defined phenotypic readouts; embryonic lethality robustly established\",\n      \"pmids\": [\"19578015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mutant PRPF31 protein (A216P) forms cytoplasmic aggregates in RPE cells, sequestering normal PRPF31 into insoluble fractions and reducing nuclear PRPF31 levels; in response, the HSP70 family chaperone Hspa4l is overexpressed and may facilitate folding and nuclear translocation of mutant protein. Co-expression of mutant and wild-type PRPF31 in vitro shows the mutant recruits normal protein into insoluble aggregates, supporting a combined haploinsufficiency/dominant-negative mechanism.\",\n      \"method\": \"Mouse model analysis (Prpf31A216P); immunofluorescence; biochemical fractionation (soluble/insoluble); in vitro co-overexpression; Western blot\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — in vivo and in vitro protein aggregation evidence; single lab with multiple methods\",\n      \"pmids\": [\"31892304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PRPF31 knockdown by siRNA in HBV-replicating cells decreased cccDNA formation without major cytotoxicity; siRNA-resistant PRPF31 rescued cccDNA formation; chromatin immunoprecipitation and immunoprecipitation assays revealed a physical association between PRPF31 and HBV cccDNA; co-overexpression of PRPF31 and HBx enhanced cccDNA formation, suggesting PRPF31–HBx interaction promotes cccDNA production.\",\n      \"method\": \"siRNA knockdown; rescue experiment with siRNA-resistant PRPF31; ChIP assay; co-immunoprecipitation; overexpression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — ChIP and co-IP plus functional rescue; single lab; novel role outside canonical splicing\",\n      \"pmids\": [\"27864147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Luciferase reporter assays identified core promoter elements for PRPF31; one functional polymorphism in the PRPF31 promoter increased transcriptional activation; a patient regulatory-region mutation reduced promoter activity by >50%, establishing a mechanism of functional haploinsufficiency at the transcriptional level.\",\n      \"method\": \"Dual-luciferase reporter assay in HeLa and RPE-1 cells; patient-derived genomic DNA constructs\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — reporter assay with patient-derived constructs; single lab, single method type\",\n      \"pmids\": [\"22723017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In fission yeast (S. pombe), Prp31 is complexed with Prp1 and Brr2 in large pre-catalytic spliceosomal particles (30S–60S) containing all five snRNAs; Prp1 and Prp31 co-sediment in the same particles, and cells lacking Prp1 still contain these Prp31-associated particles, suggesting Prp31 participates in pre-catalytic spliceosome assembly independently of Prp1 phosphorylation.\",\n      \"method\": \"Co-sedimentation/sucrose gradient fractionation; co-immunoprecipitation; genetic suppressor analysis in S. pombe\",\n      \"journal\": \"Current genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — biochemical co-fractionation plus genetic interaction in fission yeast ortholog\",\n      \"pmids\": [\"16133344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"In fission yeast, prp31+ is essential for vegetative growth and meiotic progression; a temperature-sensitive prp31-E1 allele displays pre-mRNA splicing defects and is synthetically lethal with prp6, establishing Prp31 as a general splicing factor functioning in both vegetative and meiotic contexts.\",\n      \"method\": \"Temperature-sensitive mutant isolation; complementation cloning; synthetic lethality assay with prp6; pre-mRNA splicing assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (synthetic lethality with prp6) plus in vivo splicing assay in fission yeast ortholog\",\n      \"pmids\": [\"10871341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AAV-mediated delivery of wild-type PRPF31 to iPSC-derived RPE cells from PRPF31-mutant patients restored normal phagocytosis and cilia formation, and partially restored cell structure and barrier function, demonstrating that increasing wild-type PRPF31 protein levels is sufficient to rescue RPE functional defects.\",\n      \"method\": \"AAV gene augmentation in iPSC-derived RPE; phagocytosis assay; ciliogenesis assay; transepithelial resistance measurement; immunofluorescence\",\n      \"journal\": \"Molecular therapy. Methods & clinical development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional rescue with defined cellular phenotypes in patient-derived cells; single lab\",\n      \"pmids\": [\"31890732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AAV-mediated PRPF31 gene augmentation in a CRISPR/Cas9-based Prpf31 knockout mouse model restored retinal structure and function (ERG responses), providing the first in vivo proof-of-concept for AAV gene therapy to treat PRPF31-retinitis pigmentosa.\",\n      \"method\": \"AAV-CRISPR/Cas9 knockout mouse model; AAV-PRPF31 gene augmentation; ERG; OCT; histology\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gene therapy rescue in de novo mouse model with functional and structural readouts\",\n      \"pmids\": [\"36509783\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRPF31 encodes an essential U4/U6 snRNP component whose Nop domain binds a composite RNP platform formed by the 15.5K protein and U4 (or U4atac) snRNA; it bridges U4/U6 and U5 snRNPs to enable U4/U6.U5 tri-snRNP assembly, a process regulated by PRP19-mediated K63-ubiquitination and USP15/SART3-mediated deubiquitination of PRPF31; heterozygous loss-of-function mutations cause retinitis pigmentosa primarily through haploinsufficiency (NMD of mutant transcripts, nuclear translocation defects, or protein aggregation that sequesters wild-type protein), with penetrance modulated by wild-type allele expression levels controlled in part by the transcriptional repressor CNOT3; additionally, PRPF31 has a splicing-independent role in mitosis by directly binding spindle microtubules and the Ndc80 kinetochore complex to regulate chromosome segregation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PRPF31 is an essential pre-mRNA splicing factor that bridges the U4/U6 di-snRNP to U5 snRNP, enabling assembly of the catalytic U4/U6.U5 tri-snRNP required for spliceosome activation. Its Nop domain recognizes a composite ribonucleoprotein surface formed by the 15.5K protein and U4 (or U4atac) snRNA, with specificity governed by structural differences in the snRNA capping pentaloop, and its activity is regulated by PRP19-mediated K63-linked ubiquitination and USP15/SART3-mediated deubiquitination that control its interaction with the U5 component PRP8 [PMID:17412961, PMID:21784869, PMID:28088760, PMID:15257298]. Beyond splicing, PRPF31 directly binds spindle microtubules and the Ndc80 kinetochore complex during mitosis to promote accurate chromosome segregation, a function too rapid to be explained by transcript-level effects [PMID:30475206]. Heterozygous loss-of-function mutations cause autosomal dominant retinitis pigmentosa (RP11) primarily through haploinsufficiency—most mutations generate premature termination codons degraded by nonsense-mediated decay—with disease penetrance modulated by wild-type allele expression levels controlled in part by the transcriptional repressor CNOT3 [PMID:18317597, PMID:23144630, PMID:30315276].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing PRPF31 as an essential splicing factor: the yeast ortholog PRP31 was shown to be required for cell viability and directly needed for pre-mRNA splicing both in vivo and in vitro, defining the gene's core cellular function.\",\n      \"evidence\": \"Temperature-sensitive mutant screen with in vivo and in vitro splicing assays in S. cerevisiae\",\n      \"pmids\": [\"8604353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human ortholog function not yet tested\", \"Position within spliceosomal subcomplex unknown\", \"No structural information\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Genetic interaction with PRP6 and essentiality in both vegetative and meiotic contexts were established in fission yeast, positioning Prp31 as a general splicing factor with functional links to tri-snRNP assembly components.\",\n      \"evidence\": \"Synthetic lethality of prp31 with prp6 and splicing assays in S. pombe\",\n      \"pmids\": [\"10871341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical basis of Prp31–Prp6 interaction unresolved\", \"Whether meiotic defect is direct or secondary to splicing failure unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The question of how RP11 mutations cause disease was addressed: missense mutations A194E and A216P impair nuclear translocation without exerting dominant-negative effects on splicing, pointing to protein insufficiency rather than toxic gain-of-function.\",\n      \"evidence\": \"Yeast complementation, mammalian immunofluorescence, and rhodopsin minigene splicing assay\",\n      \"pmids\": [\"12444105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of nuclear import failure not defined\", \"Whether all RP11 mutations act via same mechanism unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"PRPF31's specific role in tri-snRNP biogenesis was defined: its depletion blocks the U4/U6-to-U4/U6.U5 transition, causing U4/U6 di-snRNP accumulation in Cajal bodies, establishing PRPF31 as the bridge between di-snRNP and U5 snRNP.\",\n      \"evidence\": \"RNAi knockdown in HeLa cells with glycerol gradient fractionation and fluorescence microscopy\",\n      \"pmids\": [\"15257298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding partners mediating the bridging step not identified\", \"Role of Cajal body accumulation unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linking PRPF31 dysfunction to retinal gene expression: mutant PRPF31 inhibits splicing of rhodopsin transcripts and causes photoreceptor apoptosis, providing the first direct mechanistic connection between a ubiquitous splicing factor mutation and retina-specific pathology.\",\n      \"evidence\": \"Immunoprecipitation of splicing complexes with RT-PCR and apoptosis assays in primary retinal cells\",\n      \"pmids\": [\"15659613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why retinal transcripts are selectively vulnerable not explained\", \"In vivo retinal splicing defects not yet demonstrated\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Structural basis of PRPF31 RNA recognition was solved: the Nop domain crystal structure in complex with 15.5K and U4 snRNA revealed it as a dedicated RNP-binding module with distinct RNA and protein interaction surfaces, and RP11 mutations were linked to aberrant PRPF6 interaction.\",\n      \"evidence\": \"X-ray crystallography of the ternary hPrp31–15.5K–U4 snRNA complex; yeast two-hybrid analysis of RP11 mutants\",\n      \"pmids\": [\"17412961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length PRPF31 structure not available\", \"Structural basis of PRPF31–PRPF6 interaction not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The haploinsufficiency mechanism was firmly established: most RP11 mutations create premature stop codons degraded by NMD, producing functional null alleles, confirming that disease arises from reduced wild-type protein rather than toxic mutant protein.\",\n      \"evidence\": \"Allele-specific mRNA quantification with NMD inhibition in patient-derived cell lines\",\n      \"pmids\": [\"18317597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why 50% protein reduction is pathogenic specifically in retina not resolved\", \"Contribution of rare dominant-negative mutations not fully excluded\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Dual snRNA specificity was structurally explained: U4 and U4atac pentaloops adopt distinct conformations when bound to PRPF31–15.5K, with U4atac forming additional contacts including His270 stacking, explaining how PRPF31 serves both major and minor spliceosomes.\",\n      \"evidence\": \"X-ray crystallography of both ternary complexes with mutagenesis and gel-shift validation\",\n      \"pmids\": [\"21784869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequences of differential affinity for U4 vs U4atac in vivo not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The long-standing puzzle of incomplete RP11 penetrance was solved: CNOT3 was identified as a transcriptional repressor of PRPF31, with lower CNOT3 levels in asymptomatic carriers permitting higher wild-type allele expression that compensates for the null allele.\",\n      \"evidence\": \"ChIP showing CNOT3 binding to PRPF31 promoter; siRNA knockdown of CNOT3 increasing PRPF31 expression; correlation in patient-derived cell lines\",\n      \"pmids\": [\"23144630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other trans-acting modifiers of PRPF31 expression not surveyed\", \"Mechanism of CNOT3 expression variation between individuals unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Post-translational regulation of PRPF31 was uncovered: PRP19-mediated K63-ubiquitination and USP15/SART3-mediated deubiquitination control PRPF31's interaction with PRP8 and thus tri-snRNP stability and splicing efficiency.\",\n      \"evidence\": \"In vitro ubiquitination and deubiquitinase assays, co-immunoprecipitation, and splicing assays\",\n      \"pmids\": [\"28088760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific ubiquitinated lysine residues on PRPF31 not mapped\", \"Whether ubiquitination status is dynamically regulated across the cell cycle unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A splicing-independent mitotic function was discovered: PRPF31 directly binds spindle microtubules and the Ndc80 kinetochore complex during M phase, and its acute inhibition by antibody injection causes immediate chromosome segregation defects too rapid to reflect splicing changes.\",\n      \"evidence\": \"Antibody injection in Drosophila embryos; RNAi in HeLa cells; co-IP and microtubule co-sedimentation; M-phase-restricted interaction\",\n      \"pmids\": [\"30475206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PRPF31–Ndc80 interaction not determined\", \"Whether this mitotic role contributes to RP11 pathology unknown\", \"Mechanism of cell-cycle-restricted interaction not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Tissue-specific splicing programmes disrupted by PRPF31 haploinsufficiency were mapped: retinal cells show mis-splicing of splicing factor genes themselves, while RPE cells show mis-splicing of ciliogenesis and adhesion genes with corresponding functional defects rescued by gene editing.\",\n      \"evidence\": \"RNA-seq of patient-derived retinal organoids and RPE; Prpf31+/- mouse retina; CRISPR/Cas9 rescue\",\n      \"pmids\": [\"30315276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why splicing factor transcripts are selectively vulnerable in retinal neurons not mechanistically explained\", \"Contribution of individual mis-spliced transcripts to degeneration not isolated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Protein aggregation was identified as an additional pathogenic mechanism: the A216P mutant forms cytoplasmic aggregates that sequester wild-type PRPF31 into insoluble fractions, supporting a combined haploinsufficiency/dominant-negative model for missense mutations.\",\n      \"evidence\": \"Biochemical fractionation and co-overexpression in Prpf31-A216P mouse model and in vitro\",\n      \"pmids\": [\"31892304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Aggregation not demonstrated for other RP11 missense mutations\", \"Whether chaperone (Hspa4l) upregulation is protective in vivo not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Therapeutic proof-of-concept was achieved: AAV-mediated PRPF31 gene augmentation restored retinal structure and function in a CRISPR-generated Prpf31 knockout mouse, validating haploinsufficiency as the targetable disease mechanism.\",\n      \"evidence\": \"AAV-PRPF31 delivery in Prpf31 KO mice with ERG, OCT, and histological readouts\",\n      \"pmids\": [\"36509783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term durability of AAV-mediated rescue not established\", \"Optimal therapeutic window and dose–response not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include how PRPF31's mitotic kinetochore function relates to retinal disease, which specific retinal transcripts are rate-limiting for photoreceptor survival under haploinsufficiency, and whether the ubiquitination cycle is a druggable axis for modulating tri-snRNP assembly.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of full-length PRPF31 in the context of the human tri-snRNP\", \"Mechanism by which retinal cells are uniquely sensitive to 50% reduction unknown\", \"Relationship between mitotic and splicing functions not dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4, 7]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 3, 9, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [10, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 12, 22]}\n    ],\n    \"complexes\": [\n      \"U4/U6 di-snRNP\",\n      \"U4/U6.U5 tri-snRNP\",\n      \"15.5K–U4 snRNA ternary complex\"\n    ],\n    \"partners\": [\n      \"SNU13\",\n      \"PRPF6\",\n      \"PRPF8\",\n      \"USP15\",\n      \"SART3\",\n      \"PRPF19\",\n      \"NDC80\",\n      \"CNOT3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}